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Background and Aims Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM-1, induced remission in patients with moderate-to-severe ulcerative colitis [UC] in the TURANDOT study. We aimed to assess long-term safety, tolerability, and efficacy of ontamalimab in TURANDOT II. Methods TURANDOT II was a phase 2, multicentre, open-label [OL] study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab (NCT01771809). Patients were randomised to 75 mg or 225 mg ontamalimab every 4 weeks for 72 weeks [OL1]. The dosage could be increased to 225 mg from Week 8 at the investigator’s discretion. All patients then received 75 mg every 4 weeks for 72 weeks [OL2], followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events [AEs], serious AEs [SAEs], and AEs leading to withdrawal. Mucosal healing [MH; centrally read endoscopy] was assessed. Results Of 330 patients, 180 completed OL1; 94 escalated to 225 mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE [10.0%] was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis [0.9%]. One death and four cancers [all unrelated to ontamalimab] occurred. No PML [progressive multifocal leukoencephalopathy]/lymphoproliferative disorders occurred. Geometric mean high-sensitivity C-reactive protein [hsCRP] and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned to placebo in TURANDOT achieving MH increased from 8.8% [6/68] at baseline to 35.3% at Week 16 [24/68; non-responder imputation]. The corresponding increase in the ontamalimab group was from 23.3% [61/262] to 26.7% [70/262]. Conclusions Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.

Introduction Rabbit antithymocyte globulin (rATG) dosing strategies for induction in pediatric kidney transplantation vary between centers. It is not known whether a lower rATG induction dose provides safe and effective immunosuppression compared with a “standard” higher dose. Methods We performed a retrospective multicenter study of all isolated first-time kidney transplant recipients 4.5 mg/kg) exposure groups. Outcomes examined included 12 months posttransplant graft function (estimated glomerular filtration rate [eGFR]); the occurrence of acute rejection, donor-specific antibody (DSA), neutropenia, and viral infection (cytomegalovirus [CMV], Epstein-Barr virus [EBV], and BK virus); and 24-month outcomes of posttransplant lymphoproliferative disorder (PTLD) occurrence and patient and graft survival. Results Two hundred thirty-five patients were included. Baseline features of the low and standard rATG dose groups were similar. By 12 months, the rATG dose group had no significant impact on the occurrence of neutropenia, positive DSA, or viral polymerase chain reaction (PCR). Graft function was similar. Acute rejection rates were similar at 17% (low dose) versus 19% (standard dose) (P = 0.13). By 24 months, graft survival (96.4% vs. 94.6%) and patient survival (100% vs. 99.3%) were similar between the low- and standard-dose groups (P = 0.54 and 0.46), whereas the occurrence of PTLD trended higher in the standard-dose group (0% vs. 2.6%, P = 0.07). Conclusion A low rATG induction dose ≤ 4.5 mg/kg provided safe and effective outcomes in this multicenter low immunologic risk pediatric cohort. Prospective studies are warranted to define the optimal rATG induction dose in pediatric kidney transplantation., Graphical abstract

This paper reviews the current status of the newer inverted internal limiting membrane flap technique for macular hole surgery. It gives an overview of the importance of patient selection and special considerations along with variations in technique. It discusses the pathophysiology and how the technique has been an important addition in the armamentarium of vitreoretinal surgeons to attain better anatomical as well as functional results in challenging situations.

To establish novel and effective treatment combinations for chronic myelomonocytic leukemia (CMML) preclinically, we hypothesized that supplementation of CMML cells with the human oncogene Meningioma 1 (MN1) promotes expansion and serial transplantability in mice, while maintaining the functional dependencies of these cells on their original genetic profile. Using lentiviral expression of MN1 for oncogenic supplementation and transplanting transduced primary mononuclear CMML cells into immunocompromised mice, we established three serially transplantable CMML-PDX models with disease-related gene mutations that recapitulate the disease in vivo. Ectopic MN1 expression was confirmed to enhance the proliferation of CMML cells, which otherwise did not engraft upon secondary transplantation. Furthermore, MN1-supplemented CMML cells were serially transplantable into recipient mice up to 5 generations. This robust engraftment enabled an in vivo RNA interference screening targeting CMML-related mutated genes including NRAS, confirming that their functional relevance is preserved in the presence of MN1. The novel combination treatment with azacitidine and the MEK-inhibitor trametinib additively inhibited ERK-phosphorylation and thus depleted the signal from mutated NRAS. The combination treatment significantly prolonged survival of CMML mice compared to single-agent treatment. Thus, we identified the combination of azacitidine and trametinib as an effective treatment in NRAS-mutated CMML and propose its clinical development.

Polypoidal choroidal vasculopathy (PCV) is increasingly recognized as an important cause of exudative maculopathy in Asians as against Wet age-related macular degeneration in Caucasians. A panel of retinal experts methodically evaluated pertinent updated literature on PCV with thorough PubMed/MEDLINE search. Based on this, the panel agreed upon and proposed the current consensus recommendations in the diagnosis (clinical and imaging), management and follow-up schedule of PCV. Diagnosis of PCV should be based on the gold standard indocyanine green angiography which demonstrates early nodular hyperfluorescence signifying the polyp with additional features such as abnormal vascular network (AVN). Optical coherence tomography is an excellent adjuvant for diagnosing PCV, monitoring disease activity, and decision-making regarding the treatment. Current treatment modalities for PCV include photodynamic therapy, anti-vascular endothelial growth factor agents, and thermal laser. Choice of specific treatment modality and prognosis depends on multiple factors such as the location and size of PCV lesion, presence or absence of polyp with residual AVN, amount of submacular hemorrhage, presence or absence of leakage on fundus fluorescein angiography, visual acuity, and so on. Current recommendations would be invaluable for the treating physician in diagnosing PCV and in formulating the best possible individualized treatment strategy for optimal outcomes in PCV management.

Introduction:There have been significant improvements in both treatment and screening efforts for many types of cancer over the past decade. However, the effect of these advancements on the survival of cancer patients is unknown, and many question the value of both new treatments and screening efforts.Methods:This study uses a retrospective analysis of SEER Registry data to quantify reductions in mortality rates for cancer patients diagnosed between 1997 and 2007. Using variation in trends in mortality rates by stage of diagnosis across cancer types, we use logistic regression to decompose separate survival gains into those attributable to advances in treatment versus advances in detection. We estimate the gains in survival due to gains in both treatment and detection overall and separately for 15 of the most common cancer types.Results:We estimate that 3-year cancer-related mortality of cancer patients fell 16.7% from 1997 to 2007. Overall, advances in treatment reduced mortality rates by approximately 12.2% while advances in early detection reduced mortality rates by 4.5%. The relative importance of treatment and detection varied across cancer types. Improvements in detection were most important for thyroid, prostate and kidney cancer. Improvements in treatment were most important for non-Hodgkins lymphoma, lung cancer and myeloma.Conclusion:Both improved treatment options and better early detection have led to significant survival gains for cancer patients diagnosed from 1997 to 2007, generating considerable social value over this time period.

Objectives Malnutrition is predictor of morbidity and mortality in patients with cirrhosis. We investigated prevalence of malnutrition and factors affecting dietary intake in patients with cirrhosis. Methods Single-center cross-sectional observational study. A total of 251 patients with cirrhosis underwent dietary and nutritional assessment by subjective global assessment (SGA) and anthropometric measurement (dry body mass index, midarm circumference, midarm muscle circumference, triceps skinfold thickness, handgrip strength). Dietary intake was assessed in terms of total calories and protein intake, percentage of recommended intake, and per kilogram body weight per day. Factors influencing dietary intake were also assessed. Results Of 251 patients 199 (79%) were male and 52 (21%) were female (mean age, 51 ± 14 y, Child's A:B:C: 83:116:52). In SGA analysis 87 (35%) were well nourished (SGA-A), 106 (42%) were moderately nourished (SGA-B), and 58 (23%) were severely malnourished (SGA-C). Patients with Child's C score were severely malnourished compared with patients with Child's B and A scores. Midarm circumference, midarm muscle circumference, triceps skinfold thickness, and handgrip strength were significantly higher in SGA-A than SGA-B and SGA-C. Patients in SGA-A (1939 ± 479 kcal/d) consumed significantly higher calories than SGA-B (1494 ± 216 kcal/d) and SGA-C (1321 ± 213 kcal/d). Percentage of recommended calories intake (SGA-A [76%], SGA-B [61%], SGA-C [59%], P = 0.001) and calories/kg/d is also higher in SGA-A than SGA-B and SGA-C. The results with protein intake were similar (SGA-A [61 ± 14 gm/d], SGA-B [56 ± 7 gm/d], SGA-C [51 ± 9 gm/d], P = 0.001). Protein intake in g/kg/d is significantly lower in SGA-C (0.76 ± 0.22) than SGA-B (0.85 ± 0.2) and SGA-A (0.93 ± 0.2). A total of 61% patients were vegetarian, and 84% did not take evening snacks. Poor appetite (n = 68, 27%), early satiety (n = 75, 30%), abdominal fullness (n = 62, 25%), low-salt diet (n = 52, 21%), and social myth about diet 43(17%) were the common reasons for poor intake. Distension of abdomen, social myth about diet, and low sodium in diet were key factors affecting dietary intake in patients with cirrhosis and malnutrition. Conclusions Malnutrition seen in 65% of patients. Total calories and protein intake was significantly low compared with recommendation even in well-nourished patients. Distension of abdomen, social myth about diet, and low sodium in diet were key factors affecting dietary intake in patients with cirrhosis and malnutrition.

Introduction The intravascular ventricular assist system (iVAS) is the first minimally invasive, long-term, ambulatory counter-pulsation device that is currently being investigated as a bridge-to-transplant option for patients with advanced heart failure (HF). Ventricular tachycardia (VT) is a common complication in patients with advanced HF. Catheter ablation with substrate modification is an effective management strategy. We describe, to the best of our knowledge, the first reported case of VT ablation in a patient with the NuPulse iVAS device. Case An 82-year-old male came to the ED as his defibrillator discharged 4 times over 48 hours. He had a past history of ACC/AHA Stage D HFrEF (EF of 35%) due to ischemic cardiomyopathy. Given his advanced HF, he was enrolled in the iVAS trial and was implanted in 2019. On arrival, his BP was 172/99 mmHg and HR was 114/min. He was mildly hypervolemic on exam. CXR revealed mild pulmonary vascular congestion (Fig. 1B). ECG showed VT with a rate of 120/min (Fig. 1A). He was given IV procainamide, which transiently converted him to his baseline ventricular-paced rhythm, and his ICD was re-programmed to pace-terminate VT > 102/min. He was then loaded with IV lidocaine. Yet, he continued to have runs of VT. The next day, he underwent an adenosine nuclear stress test which showed a large severe fixed defect in the inferior and inferolateral regions suggestive of scar (Fig 1C). The following day, he underwent a VT ablation. A trans-septal approach was used to enter the LV and the scar was mapped (Fig 1D & E). Interestingly, every time radiofrequency ablation was delivered, there was electromagnetic interference with the iVAS device ECG leads which caused it to turn off. The patient became hypotensive during these episodes and dobutamine was used intra-procedurally for ionotropic support. Ablation was delivered in short bursts to allow the iVAS device to function intermittently, which prolonged the procedure time. The patient tolerated the procedure well and he has not had any recurrent VT. Discussion Long term mechanical circulatory support devices are an exciting emerging field. Complications of advanced HF include VT which is often difficult to control with medication alone and benefits from ablation. However, it appears that electromagnetic interference from radiofrequency ablation delivery impairs function of the iVAS ECG leads which gate the inflation & deflation of the counter-pulsation balloon to the cardiac cycle. Future iterations of the device must consider alternative triggers, such as being able to connect the device's ECG input to surface electrodes which would not be compromised during ablation delivery.

Purpose: To describe a bimanual technique, “tug of war” for managing anterior circumferential proliferative vitreoretinopathy (PVR) in eyes with recurrent retinal detachment (RRD). Methods: We retrospectively analyzed outcomes from eyes with RRD that underwent reattachment surgery using this maneuver and had a minimum of 6 months follow-up. A chandelier light was inserted for endo-illumination and the circumferential anterior PVR was tackled with two 25-gauge forceps stretching circumferential tractional membranes in opposite direction (tug of war) till they snapped. Results: Eleven eyes of 11 patients with a mean age of 38.2 ± 19.7 years underwent surgery. All eyes had advanced PVR of Grade C A Type 4 (Circumferential). The median duration of RD from the time of first surgery was 6 months (interquartile range = 3–8 months). The tug of war maneuver was successful in relieving the anterior retinal traction leading to retinal reattachment in all eyes without the need for relaxing retinotomies or retinectomies. Small iatrogenic retina tears occurred at the time of tug of war maneuver in 3 (27%) eyes at the site of maximum traction. The mean best-corrected visual acuity (BCVA) improved from 1.87 ± 0.2 logarithm of minimum angle of resolution (logMAR) to 1.3 ± 0.4 logMAR at 6-months follow-up (P = 0.04). Conclusion: The 'tug of war' maneuver is useful for relieving circumferential anterior traction and reattaching the retina in eyes with RRD without having to resort to large relaxing retinotomies or retinectomies.

Direct perfluorocarbon liquid (PFCL)-silicone oil exchange presents its own set of challenges in the micro incision vitreous surgery era. We propose a simple bimanual technique to circumvent this problem. Thirteen eyes of patients with retinal detachment associated with giant retinal tears underwent vitrectomy followed by self-retaining endo illuminator (Chandelier) assisted direct PFCL-silicone exchange. No intra or postoperative complications related to the surgical technique were noted. All patients had attached retinas and satisfactory visual recovery at 6 months. Direct bimanual PFCL silicone oil exchange using a Chandelier seems to be a safe and effective technique.

PURPOSE To evaluate the visual and anatomical outcomes and safety of bimanual microincision vitreous surgery for severe proliferative diabetic retinopathy. METHODS Retrospective review of 315 eyes of 282 patients who underwent 23-gauge or 25-gauge pars plana vitrectomy with bimanual membrane dissection for diabetic tractional detachment from January 2007 to September 2016. Minimum follow-up was 3 months, and the average duration of follow-up was 23 months (range 3-100 months; median 15 months). Outcome measures were best-corrected visual acuity, anatomical success, and postoperative complications. RESULTS Postoperatively, 84.3% of eyes improved (>2 lines), 10.5% were stable, and 5.4% worsened (>2 lines). Comparing gauges, two-line improvement was seen in 87.4% of 23-gauge eyes compared with 79.7% of 25-gauge eyes (P = 0.029). Mean peak best-corrected visual acuity improved from 20/930 (1.67 ± 0.63) preoperatively to 20/120 (0.78 ± 0.63) postoperatively (P < 0.001). Primary reattachment was achieved in 310 eyes (98.4%) and final reattachment in 312 eyes (99%). Recurrent vitreous hemorrhage was the commonest postoperative complication (18.4%). Lower incidence of recurrent vitreous hemorrhage was seen with 25 gauge (13.5%) compared with 23 gauge (22%, P = 0.038). Epiretinal membrane formation (7.9%), intractable glaucoma (2.5%), and endophthalmitis (0.6%) were some of the other postoperative complications. CONCLUSION Sustained visual improvement, anatomical restoration, and low complication rates were obtained in complex situations with bimanual microincision vitreous surgery in a large series. Visual outcomes were poorer in older age group, tractional retinal detachments involving macula, and eyes with extensive membranes and with silicone oil as tamponade. Both 23-gauge and 25-gauge groups were comparable in relation to visual improvement, anatomical success, and intraoperative and postoperative complications.

Reduced number of teeth with underdeveloped alveolar ridges poses a greatest prosthetic challenge in rehabilitation of ectodermal dysplasia patients (ED). Furthermore, surgical risks and financial constraints may preclude the implant supported prosthesis, the most desirable treatment option in an adult ED patient. Long edentulous span does not permit fixed dental prosthesis (FDP) as well. Telescopic denture by incorporating the best of both fixed and removable prosthesis can be a viable treatment alternative for ED patients with compromised dentition and limited finances. A 21-year-old young girl presented with chief complaint of esthetics and mastication due to missing upper and lower teeth. A provisional diagnosis of ED was made based on familial history, physical, and oral examination. This clinical report describes management of an adult ED patient by means of telescopic overdenture prosthesis in mandibular arch and FDP in maxillary arch which restored esthetics, function, and social confidence of the patient in a cost effective manner.

BACKGROUND: To report patients with age-related macular degeneration and atypical central retinal pigment epithelium (RPE) defects not attributable to geographic atrophy (GA) or RPE-tears with overlying preserved photoreceptor layers.METHODS: Multimodal imaging case-series evaluating the course of atypical RPE- defects in patients with AMD using Color fundus images, Optical coherence tomography (OCT), OCT-Angiography, fundus autofluorescence (FAF) and fluorescein-angiography (FA).RESULTS: Ten patients were identified. Three patients had a prior RPE-rip and were excluded. Seven patients with a mean follow-up period of 47 ± 38 months after the occurrence of the RPE-defect were included (age range 71-87 years). Mean distance Best corrected visual acuity (BCVA) at initial presentation was 0.36 ± 0.29logMAR and at last follow-up visit 0.51 ± 0.43logMAR. Patients presented with clinically apparent GA on funduscopy and FAF, but preserved photoreceptor layers on optical coherence tomography (OCT). On FA there was early hyperfluorescence and late pooling visible. Over time, migration of RPE/drusenoid material right above the Bruch's membrane with concomitant decrease of hypoautofluorescence was detectable in 4 cases. An enlargement of the RPE-defect was apparent in the remaining 3 cases. The majority (n = 4) showed a drusenoid pigment epithelium detachment (PED) preceding the lesion.CONCLUSIONS: Beside GA and characteristic RPE-tears, another atypical form of RPE-defect with overlying preserved photoreceptor layers are found in AMD. This so far disregarded subgroup of patients present with reasonable visual function and long-term survival of photoreceptors layers. Repair mechanisms such as ingrowth of RPE/drusenoid material and persistent subretinal fluid (SRF), but also a RPE-independent visual cycle for cone photopigment within the neurosensory retina may contribute to their favorable course.

Geriatrics is a medical practice that addresses the complex needs of older patients and emphasizes maintaining functional independence even in the presence of chronic disease. Treatment of geriatric patients requires a different strategy and is very complex. Geriatric medicines aim to promote health by preventing and treating diseases and disabilities in older adults. Development of effective dietary interventions for promoting healthy aging is an active but challenging area of research because aging is associated with an increased risk of chronic disease, disability, and death. Aging populations are a global phenomenon. The most widespread conditions affecting older people are hypertension, congestive heart failure, dementia, osteoporosis, breathing problems, cataract, and diabetes to name a few. Decreased immunity is also partially responsible for the increased morbidity and mortality resulting from infectious agents in the elderly. Nutritional status is one of the chief variables that explains differences in both the incidence and pathology of infection. Elderly people are at increased risk for micronutrient deficiencies due to a variety of factors including social, physical, economic, and emotional obstacles to eating. Thus there is an urgent need to shift priorities to increase our attention on ways to prevent chronic illnesses associated with aging. Individually, people must put increased efforts into establishing healthy lifestyle practices, including consuming a more healthful diet. The present review thus focuses on the phytochemicals of nutraceutical importance for the geriatric population., Graphical abstract

End-stage heart failure patients are being supported with continuous flow left ventricular assist devices (CF-LVAD) in increasing numbers. The severe physiologic and pharmacologic derangements associated with end-stage heart failure therapies predispose these patients to delirium. During a delirious episode, a patient may inadvertently disconnect CF-LVAD equipment, which may have dangerous consequences. Unfortunately, it is not yet routine to use readily available clinical monitoring tools to allow early detection of delirium in this high-risk population. The authors present a case of acute hyperactive delirium leading to pump power disconnection and cardiopulmonary arrest occurring 7 days after CF-LVAD implantation. The case highlights the need for delirium awareness in the cardiovascular intensive care unit and the unique challenges associated with resuscitation of CF-LVAD patients. The authors propose that cardiovascular intensive care unit patients undergo at least twice daily delirium monitoring and provide a novel resuscitation algorithm for patients who have CF-LVADs.

Background: Approximately 40% of AML patients with IDH1 mutation respond to monotherapy with the IDH1 inhibitor ivosidenib with a median duration of response of 8.2 months, suggesting that IDH1 inhibitors should be rationally combined with other agents to improve efficacy. We have previously shown the synergistic activity of the mutant IDH1 (mIDH1) inhibitor BAY1436032 with azacitidine. We have also shown that the leukemogenic activity of the mIDH1 protein depends on PHD3 independent of R-2HG and its inhibition as a novel therapeutic strategy (Chaturvedi et al. 2018). Inhibition of Brd4 has been shown to induce rapid differentiation and death of IDH2 mutated AML mouse models (Chen et al., 2013). In the present study, we assessed the combination of either conventional chemotherapy, prolyl hydroxylase (PHD) inhibitor molidustat or bromodomain inhibitor JQ1 with BAY1436032 (BAY) in a preclinical patient-derived xenograft (PDX) model of mIDH1 AML. Methods and Results: Leukemic cells from an AML patient with mutated IDH1, NPM1, FLT3-TKD and NRAS were xenografted in immunocompromised mice. We investigated the effects of BAY in sequential (seq) or simultaneous (sim) combination with cytarabine plus doxorubicin in our mIDH1 PDX model. The control groups were treated with either vehicle, BAY (150 mg/kg once daily p.o. continuously), or chemotherapy, which consisted of cytarabine (50 mg/kg once daily days 1-5 i.v.) and doxorubicin (1 mg/kg once daily days 1-3 i.v.). The treatment was repeated once after 29 days. The test groups were treated with BAY and chemotherapy in the doses mentioned above either starting both drugs on day 1 (sim group) or starting chemotherapy on day 1 and BAY on day 6 (seq group). Treatment with BAY was stopped after 12 weeks. Leukemic cells in peripheral blood constantly increased in vehicle and chemotherapy-treated mice with median time to 50% engraftment (MT 50%) of 84 and 112 days respectively. After stop of treatment, the percentage of leukemic cells increased in the group receiving BAY1436032 (MT 50%: 252 days) and sequential combination (MT 50%: 280 days), however, the MT50% was not reached with the simultaneous treatment (P We hypothesized that combination therapy with BAY and molidustat may demonstrate superior anti-leukemic activity in comparison to single agents in the treatment of IDH1-mutant AML. mIDH1 PDX mice were treated with either vehicle, BAY at a dose of 150 mg/kg or molidustat at a dose of 10 mg/kg p.o. as monotherapy or in combination. The MT50% for Vehicle, Molidustat and BAY was 70, 70 and 182 days respectively,. However, the MT50% was significantly delayed (322 days) for the combination treatment (P Mutant IDH1 PDX mice were treated with either vehicle, BAY, BRD4 inhibitor JQ1 (50mg/kg i.p. once daily) or the combination of BAY and JQ1 for 12 weeks. JQ1 monotherapy showed a significant delay in leukemia engraftment compared to vehicle-treated mice in the first 12 weeks of treatment. During the treatment, the leukemic cells remained low in both BAY and combination treated mice but relapsed at the same time 4 weeks after the treatment had been stopped. Median survival for vehicle-treated mice was 139 days, 164 days for JQ1-treated mice, 220 days for BAY treated mice, and 242 days for the combination treatment (BAY vs combination; P=0.03). Conclusion: Similar to the combination treatment of BAY with azacitidine the concurrent administration of BAY with chemotherapy significantly improves efficacy of this combination compared to sequential administration. In addition, the combination of an IDH1 inhibitor with molidustat is a promising therapeutic approach, while the combination with the BRD4 inhibitor JQ1 did not improve the outcome compared to treatment with an IDH1 inhibitor alone. Our findings support ongoing and future clinical investigations and suggest that IDH1 inhibitors should be applied concurrently with chemotherapy. Disclosures Chaturvedi: Bayer Pharma AG, Berlin, Germany: Research Funding. Kaulfuss:Bayer Pharma AG, Berlin, Germany: Employment. Panknin:Bayer Pharma AG, Berlin, Germany: Employment. Wagner:Bayer Pharma AG, Berlin, Germany: Employment, Equity Ownership. Jeffers:Bayer Pharma AG, Whippany, NJ, USA: Employment. Haegebarth:Bayer Pharma AG, Berlin, Germany: Employment, Equity Ownership. Heuser:Synimmune: Research Funding; Bayer Pharma AG, Berlin: Research Funding.

A 61-year-old man presented with floaters in his right eye for the past 2 weeks. He had a history of poorly controlled type 2 diabetes mellitus for the past 16 years along with deranged renal function parameters. Visual acuity was 20/20 in both eyes. Fundus examination of the right eye revealed mild vitreous haemorrhage along with proliferative diabetic retinopathy showing florid retinal neovascularisation (NVE) nasal to the optic disc (figure 1A). We imaged this area of the retina with a …

Chagas heart disease (ChHD) is a common cause of dilated cardiomyopathy, particularly in the endemic areas of Central and South America. The majority of cases of Chagas disease (ChD) in the US are due to emigration of infected persons from endemic areas. Current estimates indicate that around 300

We present a case where need for intervention in the fellow eye led us to a chance discovery in a postvitrectomy, gas-filled eye. Although theoretically aware of the ability of wide field imaging through gas, we captured the images presented by sheer serendipity. A 38-year-old-man with OU proliferative diabetic retinopathy (PDR) and vitreous haemorrhage in OD underwent vitrectomy with perfluoropropane gas injection. Imaging was planned after absorption of the gas. However, 3 weeks postoperatively, he reported of seeing a floater in the unoperated eye. To perform immediate angiography-guided laser, we performed fundus fluorescein angiography (FFA) with Topcon TRC-50DX (Topcon, Tokyo, Japan) as well as on Optos (Dunfermline, Scotland). Conventional angiography captured blurred images …

Objective: Ultrasound has been proven to be useful in detecting underlying ovarian pathology. However, its role in the prediction of ovarian torsion has been controversial. The aim of the study was to assess the validity of ultrasound in the prediction of ovarian torsion in patients with acute pelvic pain related to clinically suspected ovarian torsion. Methods: A retrospective observational study was conducted at the Ob/Gyn department using a 10-year chart review of all female patients older than 11 years of age with highly suspected ovarian torsion who underwent clinical assessment and ultrasound prior to surgery (n = 62). The sensitivity and specificity of ultrasound were determined by cross-tabulation of the ultrasound and surgical findings. Results: Of the suspected cases, 54 (87.1%) were confirmed to be cases of ovarian torsion by surgery. The majority of the cases were suggestive of ovarian torsion, which was indicated by clinical examination (77.4%), ultrasound (77.4%), or pathological examination (79%). Almost one-half of the cases (46.8%) showed a pain score >6; two-thirds (62.9%) presented with vomiting and/or nausea; and more than one-third (38.7%) presented with leukocytosis. The estimated sensitivity and specificity of ultrasound were 0.74 and 0.0, respectively. The positive predictive value was 0.83. Ultrasound was significantly associated with both clinical examination (p = 0.039) and pain score (p = 0.008). Conclusion: The diagnosis of ovarian torsion cannot be exclusively based on ultrasound. Both clinical and sonographical evaluation of acute pelvic pain should be considered for the diagnosis. A definitive diagnosis remains challenging.

Michael Heuser and Anuhar Chaturvedi share senior authorship Background: Isocitrate dehydrogenase-1 (IDH1) is mutated in about 6% of AML patients. Mutant IDH produces R-2-hydroxyglutarate (R-2HG), which induces histone and DNA hypermethylation through inhibition of epigenetic regulators, thereby linking metabolism to tumorigenesis. We recently reported that at comparable intracellular R-2HG levels, mice receiving transplants of IDH1 mutant cells died significantly earlier than R-2HG treated mice in the context of HOXA9 overexpression. This suggests oncogenic functions of mutant IDH1 beyond R-2HG production. We employed a splice variant of mutated IDH1 that does not produce R-2HG (IDH1mutantΔ7) to decipher R-2HG independent signaling pathways that may contribute towards leukemogenesis. Methods: Bone marrow cells from mice were immortalized with HoxA9, and IDH1wildtype (IDH1wt), IDH1mutant (IDH1mut), IDH1wildtypeΔ7 (IDH1wtΔ7) and IDH1mutΔ7, were constitutively expressed and the leukemogenic potential was evaluated in vivo. Intracellular R-2HG was measured by enantiomer-specific quantification. Deletion of exon 7 from IDH1mut leads to a frameshift that creates a premature stop codon in the 9th exon, finally producing a 119 amino acids truncated protein, IDH1mutΔ7. This splice variant does not produce increased levels of R-2HG. The signaling pathways were explored by immunoblotting and immunofluorescence. Results: Mice receiving cells with IDH1mutΔ7 had the same short latency to leukemia as mice receiving cells with full-length mutant IDH1, while IDH1wt and IDH1wtΔ7 cells died with significantly longer latency. The WBC count increased over time in IDH1mutΔ7 mice similar to IDH1mut mice, whereas WBC counts in IDH1wtΔ7 mice remained normal. IDH1mutΔ7 mice died from monocytic leukemia that was phenotypically and morphologically indistinguishable from IDH1mut mice. HoxA9 IDH1mutΔ7 cells were readily transplantable into secondary recipients. During in vivo cell cycle analysis, we observed that the proportion of cells in S/G2/M phases was significantly higher in bone marrow cells transduced with IDH1mut or IDH1mutΔ7 when compared to cells transduced with IDH1wt or CTL. These data suggest that mutant IDH1 enhances myeloproliferation even in the absence of R-2HG. To identify R-2HG independent signaling pathways mediated by the mutant IDH1 protein, we first analyzed the gene expression of important regulators of cell cycle, differentiation, cell signaling and transcription by quantitative RT-PCR. Several genes (Ccnd1, Slc2a, Hdac3, Tgif2,and c-myc) were upregulated in IDH1mut and IDH1mutΔ7 cells compared to IDH1wt cells. Interestingly, we found a specific up-regulation of Ctnnb1 and Nfkb genes in IDH1mutΔ7 cells over both IDH1mut and IDH1wt cells. We next validated our mRNA expression results by immunoblotting and found that NFKB and ERK signaling were upregulated in both IDH1mut and IDH1mutΔ7 compared to IDH1wt and IDH1wtΔ7 cells. Interestingly, the protein level of β-catenin, STAT3 and STAT5 were many fold higher in IDH1mutΔ7 compared to IDH1mut and IDH1wt cells. β-catenin is known to be transactivated via c-Src, which is phosphorylated by EGFR to promote β-catenin nuclear localization and signaling. We traced this pathway for its relevance in our cells and found that IDH1mutΔ7 cells indeed showed higher levels of both EGFR and c-Src phosphorylation compared to IDH1mut cells. We performed immunofluorescence and cellular fractionation for β-catenin and found it to be partially localized in the nucleus in IDH1mutΔ7 but not in IDH1mut cells. We also observed an up-regulated STAT3 phosphorylation in IDH1mutΔ7 cells over IDH1mut. Conclusions: In summary, mutant IDH1 activates ERK and NFKB signaling, which is attributed to both R-2HG dependent and independent mechanisms of leukemogenesis. Interestingly, IDH1mutΔ7 employs R-2HG independent EGFR/β-catenin and JAK/STAT signaling for oncogenesis. This R-2HG-independent leukemogenesis reveals a novel signaling dynamic of IDH1mut which should be evaluated for its therapeutic potential. Disclosures Ganser: Novartis: Membership on an entity's Board of Directors or advisory committees. Heuser:Astellas: Research Funding; Karyopharm: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; StemLine Therapeutics: Consultancy; Bayer Pharma AG: Consultancy, Research Funding; Sunesis: Research Funding; BergenBio: Research Funding; Tetralogic: Research Funding; Daiichi Sankyo: Research Funding.

Conjugated fatty acid, the general term of positional and geometric isomers of polyunsaturated fatty acids with conjugated double bonds, has attracted considerable attention because of its beneficial biological effects. In the present study, dietary effect of pomegranate seed oil rich in punicic acid (9cis, 11trans, 13cis-conjugated linolenic acid; 9c, 11t, 13c-CLNA) on lipid metabolism was investigated in obese, hyperlipidemic Male albino Wistar (MAWR) rats. After 4 weeks feeding period, MAWR rats revealed obesity and hyperlipidemia compared with their progenitor AELM rats. Feeding of the diet supplemented with 9% safflower oil and 1% pomegranate seed oil (9c, 11t, 13c-CLNA diet) did not affect abdominal white adipose tissue weights and serum lipid levels compared with the diet supplemented with 10% safflower oil (control diet) in MAWR rats. However, the accumulated hepatic triacylglycerol was markedly decreased by 9c, 11t, 13c-CLNA diet in MAWR rats. Activities of hepatic enzymes related to fatty acid synthesis and fatty acid β-oxidation were not altered by 9c, 11t, 13c-CLNA diet. Levels of monounsaturated fatty acid (MUFA), major storage form of fatty acid, in serum triacylglycerol were markedly higher in obese, hyperlipidemic MAWR rats than in lean LETO rats. In addition, 9c, 11t, 13c-CLNA diet significantly decreased MUFA levels in MAWR rats. This is the first study showing that 9c, 11t, 13c-CLNA suppresses delta-9 desaturation in vivo, and we suggest that the alleviation of hepatic triacylglycerol accumulation by 9c, 11t, 13c-CLNA diet was, at least in part, attributable to the suppression of delta-9 desaturation in MAWR rats.

Current definitions of acute kidney injury (AKI) are not sufficiently sensitive to identify all newborns with AKI during the first week of life.To determine whether the rate of decline of serum creatinine (SCr) during the first week of life can be used to identify newborns with AKI, we reviewed the medical records of 106 term neonates at risk of AKI who were treated with hypothermia for hypoxic ischemic encephalopathy (HIE).Of the newborns enrolled in the study, 69 % showed a normal rate of decline of SCr to ≥50 % and/or reached SCr levels of ≤0.6 mg/dl before the 7th day of life, and therefore had an excellent clinical outcome (control group). Thirteen newborns with HIE (12 %) developed AKI according to an established neonatal definition (AKI-KIDGO group), and an additional 20 newborns (19 %) showed a rate of decline of SCr of33,40, and46 % from birth to days 3, 5, or 7 of life, respectively (delayed rise in estimated SCr clearance group). Compared to the control group, newborns in the other two groups required more days of mechanical ventilation and vasopressor drugs and had higher gentamicin levels, more fluid overload, lower urinary epidermal growth factor levels, and a prolonged length of stay.The rate of decline of SCr provides a sensitive approach to identify term newborns with AKI during the first week of life.

Lessons Learned Trebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC). In support of previously reported high Ang-2 levels’ association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2. Background Ang-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC). Methods Patients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2. Results Thirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts. Conclusion There was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.

To the Editor: Retinopathy of prematurity (ROP) still remains a challenging condition to detect, image, document and treat. Documentation has become necessary in recent times due to advancement in telemedicine, newer treatment modalities like intravitreal anti-VEGF injections [1] and medicolegal implications. It is important to note that despite advancements in imaging modalities, indirect ophthalmoscopy with scleral depression remains the gold standard for retinal evaluation in ROP management. Currently used Retcam® (Clarity Medical Systems, Inc., Pleasanton, CA) became commercially available in 1997. Retcam utilizes a contact lens with a fiberoptic cable light source connected to a computer monitor for retinal imaging. Its shortcomings include relatively limited field of view (130 degrees) [2] and being a contact system, would be avoided in the immediate post intravitreal injection period to minimize chances of infections. Optos® 200Tx scanning laser ophthalmoscope (Optos PLC, Dunfermline, Scotland) is a recently introduced noncontact ultra wide field (UWF) retinal imaging system. Optos utilizes the optics of an ellipsoid mirror, which has two focal points to create images of the peripheral retina, thereby capturing up to 200 degrees of retina in a single image [3]. Limitations of this modality include high cost of equipment and the need for the operator to be trained in its use. Due to its large size, it is not easy to transport the Optos, unlike the Retcam which is a portable device and can easily be manoeuvred into pediatric nurseries for screening purpose. Patel et al. evaluated its role in ROP babies elegantly using the Bflying baby^ position [4]. We present retinal images from a premature infant born at 27 wk who underwent laser for ROP stage 3 in zone 2. At 38 wk while the right eye shows well regressed disease (Fig. 1), the left eye shows skip areas with preretinal hemorrhage (Fig. 2) for which laser augmentation was done. We believe this to be the first report of UWF non-contact imaging for ROP from the Indian subcontinent with this new imaging modality.

This article presents the results of a 4-year follow-up of employed persons who cared for frail parents. The study 's purpose was to examine how managing the joint roles of work and caregiving changed over time. A total of 24 people still involved in full-time employment and caregiving were located. Attrition was high due to employee retirement, parental death, and nonresponses. Findings from t tests of paired means revealed a significant decline in parents'level offunctioning and significant changes in respondents' financial, social, and personal lives as well as in their job satisfaction. No significant changes were found in respondents' physical condition or in their work conditions. However, employed caregivers at time 2 were far more likely than those at time 1 to expect their workplaces to offer benefits and services that would make it easier for them to manage their joint roles. Implications of findings are discussed.

Drug discovery initiatives, aimed at Chagas treatment, have been hampered by the lack of standardized drug screening protocols and the absence of simple pre-clinical assays to evaluate treatment efficacy in animal models. In this study, we used a simple Enzyme Linked Aptamer (ELA) assay to detect T. cruzi biomarker in blood and validate murine drug discovery models of Chagas disease. In two mice models, Apt-29 ELA assay demonstrated that biomarker levels were significantly higher in the infected group compared to the control group, and upon Benznidazole treatment, their levels reduced. However, biomarker levels in the infected treated group did not reduce to those seen in the non-infected treated group, with 100% of the mice above the assay cutoff, suggesting that parasitemia was reduced but cure was not achieved. The ELA assay was capable of detecting circulating biomarkers in mice infected with various strains of T. cruzi parasites. Our results showed that the ELA assay could detect residual parasitemia in treated mice by providing an overall picture of the infection in the host. They suggest that the ELA assay can be used in drug discovery applications to assess treatment efficacy in-vivo., Author Summary A marked decrease in incidence of Chagas Disease has been observed in the last decade achieved by vector control strategies; however, there are still geographical areas where the disease reaches endemic proportions. Due to high morbidity and disease burden, other avenues of Chagas control, such as vaccines and therapeutic agents need to be employed for comprehensive disease control and mitigation. As there are no vaccines available currently, two drugs (Benznidazole and Nifurtimox) have been the mainstay of treatment. However, these drugs produce multiple side effects and frequently lead to early termination of the treatment. In this study, we have successfully developed a new method to evaluate the presence of Chagas biomarkers in the plasma of infected drug treated mice. Our study shows that high biomarker levels in T. cruzi infected mice, after drug treatment, can indicate treatment failure. Our assay provides a global picture of parasitemia in the host and a positive result would thus suggest that the treated animals continue to harbor T. cruzi parasites somewhere in the body. This study provides a new method to test for T. cruzi infection and for assessing the effectiveness of treatment.

286 Background: Trebananib is a first-in-class antiangiogenic therapy that sequesters Ang1 and Ang 2, preventing their interaction with the Tie 2 receptor. A previous study of the combination of trebananib with sorafenib in renal cell carcinoma showed an acceptable toxicity profile. Elevated Ang 2 levels have been associated with a poor prognosis in HCC. We thus evaluated the safety and efficacy of trebananib plus sorafenib in HCC. Methods: Patients with HCC, ECOG ≤ 2, Childs-Pugh A, and adequate organ function received IV trebananib at 10mg/kg weekly (cohort 1) or 15 mg/kg weekly (cohort 2) plus sorafenib 400 mg PO twice daily. Thirty patients were accrued to each cohort to provide a power of 80% with the 1-sided exact test for single proportion at α = 0.20 to show a ≥ 78% PFS rate at 4 months relative to 62% reported in the sorafenib historical control. Secondary endpoints included safety and tolerability, progression free survival, objective response rate, disease control rate, time to progression, and overall survival. Results: See table. Conclusions: Trebananib at 10 mg/kg and 15 mg/kg plus sorafenib were well tolerated in patients with advanced HCC. When compared with historical controls, study results did not show an improvement in PFS rate at four months. Clinical trial information: NCT00872014. [Table: see text]

Chagas disease affects about 5 million people across the world. The etiological agent, the intracellular parasite Trypanosoma cruzi (T. cruzi), can be diagnosed using microscopy, serology or PCR based assays. However, each of these methods has their limitations regarding sensitivity and specificity, and thus to complement these existing diagnostic methods, alternate assays need to be developed. It is well documented that several parasite proteins called T. cruzi Excreted Secreted Antigens (TESA), are released into the blood of an infected host. These circulating parasite antigens could thus be used as highly specific biomarkers of T. cruzi infection. In this study, we have demonstrated that, using a SELEx based approach, parasite specific ligands called aptamers, can be used to detect TESA in the plasma of T. cruzi infected mice. An Enzyme Linked Aptamer (ELA) assay, similar to ELISA, was developed using biotinylated aptamers to demonstrate that these RNA ligands could interact with parasite targets. Aptamer L44 (Apt-L44) showed significant and specific binding to TESA as well as T. cruzi trypomastigote extract and not to host proteins or proteins of Leishmania donovani, a related trypanosomatid parasite. Our result also demonstrated that the target of Apt-L44 is conserved in three different strains of T. cruzi. In mice infected with T. cruzi, Apt-L44 demonstrated a significantly higher level of binding compared to non-infected mice suggesting that it could detect a biomarker of T. cruzi infection. Additionally, Apt-L44 could detect these circulating biomarkers in both the acute phase, from 7 to 28 days post infection, and in the chronic phase, from 55 to 230 days post infection. Our results show that Apt-L44 could thus be used in a qualitative ELA assay to detect biomarkers of Chagas disease., Author Summary Chagas disease, caused by the parasite Trypanosoma cruzi, is a major health concern for people living in Latin America. There are no vaccines to prevent this disease and only two drugs are prescribed for treatment. Current methods to diagnose patients are not always successful and thus new methods need to be developed. One approach to develop an alternate method is to detect proteins and metabolites that are secreted by parasites into the blood of infected individuals. We have utilized a selection based method to isolate ligands that bind to these secreted proteins. These ligands, called aptamers, have been used to develop an assay that can detect the circulating parasite targets in the plasma or serum of an infected host. In an animal model of Chagas disease, our assay can detect parasite biomarkers as early as seven days after infection and as late as 230 days post infection. As the laboratory instruments and procedures are similar to performing an ELISA, the aptamer assay reported here could be easily performed at diagnostic facilities. Further improvement in this assay can lead to a new quantitative diagnostic test for Chagas disease. A similar selection based approach could also be used to develop ligands for the detection of biomarkers in other diseases.

Mutant IDH1 (mIDH1) inhibitors have shown single-agent activity in relapsed/refractory AML, though most patients eventually relapse. We evaluated the efficacy and molecular mechanism of the combination treatment with azacitidine, which is currently the standard of care in older AML patients, and mIDH1 inhibitor BAY1436032. Both compounds were evaluated in vivo as single agents and in combination with sequential (azacitidine, followed by BAY1436032) or simultaneous application in two human IDH1 mutated AML xenograft models. Combination treatment significantly prolonged survival compared to single agent or control treatment (P

4666 Background: Survival after diagnosis of metastatic prostate cancer (mPC) averages 2-3 years. Substantial regional differences in survival have been documented for PC prior to 2000. We investigated the extent to which regional variation exists in survival for mPC patients during 2000-2007. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database linked to Medicare claims, we identified men (mean age, 77.6 years) continuously enrolled in Medicare Parts A/B who were diagnosed with mPC between 2000 and 2007 and not diagnosed with another malignancy. The base-case model was limited to hospital service areas with >50 patients. A Cox proportional hazards model was used to estimate hazard ratios (HR) for overall survival (OS), adjusting for year of diagnosis, age, marital status, poverty and education covariates, Gleason score, comorbidities, and region covariates. Sensitivity of results was tested by limiting the analysis to patients surviving at least 6 months after diagnosis and by removing regional sample size limits. We report HRs for covariates, results of a Wald test of joint significance for region effects, and percentage difference from the mean for each region’s HR for death. Results: A total of 2696 patients with mPC met the inclusion criteria. OS was 37% at 3 years and mean HR for death was 4.8 (sd 2.1). HRs for death were positively correlated with age (HR=1.96, 95% CI: 1.6-2.3 for >80 years), PC-specific comorbidity index (HR=1.2, 95% CI: 1.1-1.3), and Gleason score (HR=6.6, 95% CI: 2.4-17.8 for poorly differentiated). Year of diagnosis, race, and socioeconomic status were not significantly associated with mortality. Wald test of joint significance for survival across regions of P=.019 indicated significant differences in survival across regions and was robust in sensitivity analyses. Patients living in regions with the worst survival rates had HRs for death that were 20% higher than the mean (HR=5.8) and those living in regions with the best survival rates had HRs 30% lower than the mean (HR=3.4). Conclusions: There are significant regional differences in survival for mPC patients in the 2000s. Further research is needed to determine if treatment differences play a role in this disparity.